New Technique For Identification of Molecular Determinants in Neurodegenerative Diseases

Researchers at Rockefeller University and Columbia University in New York recently reported a new technique which enabled them to identify specific molecular determinants linked to Parkinson’s disease and other neurodegenerative disorders, including spinal muscular atrophy (SMA). The study was published in the journal Nature Neuroscience and is entitled “Identification of neurodegenerative factors using translatome–regulatory network analysis”.

Parkinson’s disease is a progressive neurodegenerative disorder that develops gradually from a slight tremor of the hands to serious difficulties in speaking, locomotion, coordination and balance. The disease is caused by the loss of the neurotransmitter dopamine due to premature death of dopaminergic neurons in a brain region called substantia nigra pars compacta (SNpc). Dopaminergic neurons play an important role in voluntary movement and behavioral processes (mood, stress, reward, addiction). Interestingly, some degeneration also occurs in dopaminergic neurons in a neighboring brain region called the ventral tegmental area (VTA), although for some reason, the VTA neurons are not as affected as those on the SNpc.

In the study, researchers analyzed the molecular alterations that lead to neuron loss. “Within a dying nerve cell, the levels of hundreds of proteins change,” explained the study’s co-senior author Dr. Paul Greengard in a news release. “Some of these shifts are consequences, others are causes. We set out to find which cause cell death among neurons.”

Researchers discovered two proteins that seem to have a protective action in dopaminergic neurons; when the activity of these proteins declines, the disease develops. Dr. Greengard explained “we identified two of these so-called master regulatory molecules — a discovery that offers an unexpected explanation as to why one population of neurons degenerates in Parkinson’s, while similar neighbors do not suffer from the same degree of degeneration.”

The team adapted profiling techniques based on genetically engineered mice in order to collect genetic data for protein production in a specific population of cells. The team mapped the interactions between regulator genes and their targets in the mouse brain, and used it to interpret the alterations found in normal mice and those experiencing Parkinson’s-like degeneration.

Through this novel technique where translational profiling is combined with brain regulatory network analysis, the team identified two relevant proteins: SATB1 and ZDHHC2, which are more abundant in SNpc dopaminergic neurons than VTA. Remarkably, when the levels of these two proteins were reduced in the brains of healthy mice, researchers observed a rapid degeneration similar to the one found in Parkinson’s disease.

“Conventional gene activity profiling approaches would not have been able to identify SATB1 and ZDHHC2 as key protective factors because the levels of these proteins do not change. But even though they continue to be expressed within the neurons, it appears that their regulatory activity drops off and they no longer stimulate their target genes,” explained the study’s lead author Dr. Lars Brichta. “We later found similar changes in activity in the brains of Parkinson’s patients, particularly those in the early stages.”

“In an unexpected contradiction to current models, the proteins we found protect the SNpc. Because dopamine and its metabolites can be toxic, we can speculate that, in the course of evolution, SATB1 and ZDHHC2 arose to protect this particular set of sensitive neurons from cell death,” added Dr. Greengard. “The discovery of these two molecules’ role in Parkinson’s may assist in the development of treatments, because they are potential new targets for drugs.”

The team believes that their new technique might be a valuable resource for the identification of molecular determinants in other neurodegenerative diseases, namely spinal muscular atrophy (SMA), a rare, devastating motor neuron disease and one of the leading genetic causes of pediatric mortality, occurring in approximately 1 in every 6,000 to 10,000 newborns. SMA is characterized by the degeneration of nerves controlling muscles and voluntary movement, resulting in muscle weakness, atrophy, paralysis and eventually death.